442 Single-Cell Omics Identify Mature Pituitary Cells as the Origin of Adenomas

作者：Dhruval Bhatt, Dustin Mullaney, Debjani Mandal, Abdel Elkahloun, Dragan Maric, Prashant Chittiboina · 发表于：Neurosurgery · 年份：2026 · DOI：10.1227/neu.0000000000003964_442 · 研究领域：Pituitary Gland Disorders and Treatments、Single-cell and spatial transcriptomics、Growth Hormone and Insulin-like Growth Factors

INTRODUCTION: Pituitary adenomas affect up to 20% of the population and account for∼20% of intracranial tumors in clinical practice. Their origins remain unclear, whether from stem-like folliculostellate cells (FSCs) or mature hormone-secreting pituitary cells. METHODS: We developed microsurgical techniques to procure and annotate tumor-normal pituitary pairs from both micro- and macroadenomas. Single-cell RNA (scRNA-seq) and chromatin accessibility (scATAC-seq) profiling was performed on 12 tumor-normal pairs and 22 additional tumors, representing all major pituitary phenotypes: ACTH-, GH-, prolactin-, gonadotropin-, and non-functioning adenomas and totaling 146,994 cells. Spatial transcriptomics was conducted on 9 tumor-normal margins using a targeted 300-gene panel. To model tumorigenesis, we generated pituitary organoids from patient-derived human induced pluripotent stem cells (hiPSCs) and introduced cell-type-specific perturbations. RESULTS: Mature pituitary cells exhibited elevated single nucleotide variant burdens, suggesting predisposition to transformation. Lineage tracing of syngeneic tumor-normal pairs showed adenomas arise from terminally differentiated pituitary cells, not FSCs. SOX2- and S100B-positive FSCs were confined to the normal gland. Each tumor phenotype was traced to its corresponding mature pituitary cell type. Transcription actor activity inference using scRNA-seq and scATAC-seq identified key regulators driving transitions from normal to tumor state...